Increase, Mt Dysfunction leads to Increase, Cytotoxicity (renal tubular cell)

Mitochondria are an essential organelle in ROS production, ATP production, and have a crucial role in regulating both apoptotic and necrotic death (Bhatia, Capili, and Choi, 2020; Wang et al., 2016; Gao et al., 2019). This is particularly notable for renal tubular cells due to their high energy demands for filtration (Cohen, 1986). When mitochondria are damaged and their membrane potential is dissipated, the mitochondrial permeability transition pore (mPTP) is opened and they release cytochrome c (Cyt c), pro-apoptotic caspases, and apoptosis-inducing factor (AIF) (Mao et al., 2010; Galluzzi et al., 2018; Garrido et al., 2006). Cyt c is a protein that triggers apoptosis or necrosis by allosterically activating apoptosis-protease activating factor 1 (APAF 1) (Mao et al., 2010; Galluzzi et al., 2018; Garrido et al., 2006). APAF 1 is then able to cleave caspases 9 and 3, which lead to the induction of a caspase cascade that triggers apoptosis (Mao et al., 2010; Galluzzi et al., 2018; Garrido et al., 2006). Caspase-independent apoptosis is also triggered by the opening of the mPTP, causing the release of AIF which triggers DNA condensation into chromosomes and  degradation in a characteristic manner (Sevrioukova, 2011). Mitochondrial dysfunction therefore leads to not only further oxidative stress, but also to cell death (Bhatia, Capili, and Choi, 2020; Wang et al., 2016; Zhan et al., 2013).

There are several known modulating factors that affect the relationship between mitochondrial dysfunction and cell death. One known modulating factor of this variation is mitochondrial biogenesis (Jornayvaz and Shulman, 2010). Mitochondrial biogenesis is the ratio of growth, division, and recycling of existing mitochondria in the cell. Mitochondrial biogenesis itself is influenced by a variety of factors such as exercise levels, cell division, low temperature, caloric restriction, and as is discussed in this AOP, oxidative stress . As a result of changes in these factors, the mitochondrial content, as well as sizes and masses of each of the organelles, is altered . For example, it is generally accepted that increased exercise in an organism increases mitochondrial content and functioning, as there is an increased energy need in those organisms . Therefore, an organism with increased exercise habits would have a less steep slope in the relationship between mitochondrial dysfunction and cell death, as the mitochondrial dysfunction would not be able cause cell death as quickly, since mitochondrial content would be higher requiring a longer time period to accumulate sufficiently to induce apoptosis . This would allow the cell to undergo mitophagy of the injured mitochondria while still continuing to produce adequate energy to keep the cell alive . Similarly, if a cell had just divided, it would be less prepared and capable of dealing with mitochondrial dysfunction, which would allow it to accumulate much faster and would therefore increase the slope between mitochondrial dysfunction and cell death (Jornayvaz and Shulman, 2010).

Some diseases are also known to modulate this relationship, such as early aging and diabetes (Pizzorno, 2014). These diseases increase the slope of the relationship between mitochondrial dysfunction leading to oxidative stress due to the fact that they induce faster accumulation of mitochondrial dysfunction via increased levels of oxidative stress and faster accumulation of mitochondrial DNA damage leading to earlier mitochondrial dysfunction (Nissanka and Moraes, 2018; Zelenka, Dvorak, and Alan, 2015; Wei et al., 2015; Kudryavtseva et al., 2016; Forbes and Thorburn, 2018; Schiffer and Friederich-Persson, 2017).

The domain of applicability only includes vertebrates, as invertebrates and non-animals do not have kidneys (Mahasen, 2016).